Hexarelin (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) is a new potent synthetic growth hormone (GH)-releasing hexapeptide. The mechanism of action of hexarelin in man has never been evaluated. Hexarelin may act directly on specific pituitary receptors and indirectly on the hypothalamus. To elucidate its mechanism of action in man, we studied the interaction of hexarelin with glucose and free fatty acids (FFA), two metabolic factors known to inhibit both basal and GH-releasing hormone (GHRH) stimulated GH secretion. Glucose is thought to inhibit GH secretion via stimulation of endogenous somatostatin release, whereas FFA could also act directly on somatotrope cells. Therefore, we investigated the effect of oral glucose (100 g) and lipid-heparin infusion (250 mL of a 10% lipid solution + 2,500 U heparin) on the GH response to a maximal dose (2 micrograms/kg intravenously [IV]) of hexarelin or GHRH in six normal men. Hexarelin elicited a clear-cut GH response (mean +/- SEM; peak, 62.6 +/- 8.0 micrograms/L) that was higher (P < .01) than that observed after GHRH (peak, 19.8 +/- 2.4 micrograms/L). Although similar increases in plasma glucose were observed with the two peptides, oral glucose almost abolished the GH response to GHRH (peak, 5.6 +/- 0.9 micrograms/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 38.4 +/- 7.9 micrograms/L, P < .05). Similarly, lipid-heparin infusion nearly abolished the GH response to GHRH (peak, 4.9 +/- 1.0 micrograms/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 34.2 +/- 4.5 micrograms/L, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)